Rolle von TRPM8 und TRPA1 Kanälen bei der Regulation des Gefäßtonus

Über den endothelabhängigen Hyperpolarisation-Faktor (EDHF) induziert das Gefäßendothel eine Hyperpolarisation der direkt benachbarten Gefäßmuskelzellen und bewirkt so deren Relaxation. Gleichwohl die chemische Idendität des EDHF noch nicht geklärt ist, geht man davon aus, dass die EDHF Wirkung zunä...

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Bibliographic Details
Main Author: Kurtz, Felix
Contributors: Köhler, Ralf (Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2011
Innere Medizin
Subjects:
TRP
Online Access:PDF Full Text
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Table of Contents: The vascular endothelium induces hyperpolarization and in consequence relaxation of vascular smooth muscle cells via the generation of endothelium-derived-hyperpolarzing factor (EDHF). Although the structural identity of EDHF has not yet been unequivocally clarified, there is agreement that the generation of EDHF is initiated by the activation of calcium regulated potassium channels (KCa) in endothelial cells. The local increases of calcium required to activate KCa can be brought by several signaling pathways. One among these is the activation of calcium permeable TRP-channels in the plasma membrane of endothelial cells. Based on preliminary evidence found in the literature this work aimed to define the roles of TRPM8 and of TRPA1 channels for endothelium mediated vasodilatation by means of pharmacology and electrophysiology. It was found that the established TRPM8 channel activators menthol and icilin and the TRPA1 channel activator AITC all caused dose-dependent vasodilations of isolated perfused mouse carotid arteries. The vasodilatory effects of these drugs, however, were maintained even after mechanical removal of the endothelium, suggesting that the observed vasodilatations were not mediated by the endothelium. Moreover, the before mentioned channel activators did not induce TRP-like currents in endothelial cells isolated from mouse carotid arteries, again suggesting that TRPM8 and TRPA1 do not play major functional roles in endothelial cells. Menthol, however, induced a prominent cation current in isolated endothelial cells. Additionally menthol almost completely blocked an L-type channel like current in cultured vascular smooth muscle cells (A7R5). The latter effect likely explains the endothelium independent vasodilatation induced by menthol. In summary, the present work does not support a role of endothelial TRPM8 und TRPA1 channels for the regulation of vessel diameter and in consequence of vascular resistance.